p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway

The signaling adaptor p62 is a critical mediator of important cellular functions, owing to its ability to establish interactions with various signaling intermediaries. Here, we identify raptor as an interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1. p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation. [Display omitted] ► p62 is a component of mTORC1 complex and not mTORC2 via interaction with raptor ► p62 is required for mTORC1 activation in response to amino acids ► p62 interacts with the Rag GTPases and induces the formation of the active Rag dimer ► p62 mediates mTORC1 recruitment to lysosomes